Bibliographic details of the publications referred to by author in this specification are collected at the end of the description.
Reference to any prior art in this specification is not, and should not be taken as, an acknowledgment or any form of suggestion that this prior art forms part of the common general knowledge in Australia or any other country.
As the most common internal cancer in older men and the seventh most common cause of death in men of all ages in developed countries, cancer of the prostate is a serious health problem in terms of drawn-out personal suffering and premature death not to mention the cost to the health care system. The incidence of prostate cancer appears to be increasing, over and above improved detection rates in recent years (Post et al., 1999). Although many men with cancer of the prostate die from other causes, the high incidence results in significant morbidity and death directly from the prostatic tumor. Currently-available therapy carries a significant risk of major side effects, including incontinence and impotence, and consequently many men are reluctant to accept treatment at an early stage of the disease. The need to improve the treatment of prostate cancer is underlined by the existence of over 150 clinical trials world wide (Future Oncology, vol. 4, number 3, 1998), including 34 new or modified products (http://www.phrma.org/idf/charts/cancer99.pdf).
Hormone-resistant bony secondaries (hrbs) are universally found in the natural history of advanced prostate cancer and are resistant to all current chemotherapy. They cause severe pain, prolonged hospitalization, pathological fractures, spinal-cord compression and paraplegia, and may be fatal. External beam radiotherapy is the mainstay of palliative treatment. However, it can only be used once for a given bony secondary. A range of bone-seeking compounds can image prostate cancer metastases (Bushnell et. al., 1999; Norris et al., 1999). Parenteral strontium isotopes have had limited success for treatment but their use is limited by their toxicity to the bone narrow, especially platelets. Bisphosphonates (osteoclast inhibitors) may decrease the bone pain in a few cases, but again are generally disappointing and do not increase life expectancy.
There is a need, therefore, to develop more effective therapeutic protocols and more efficacious therapeutic agents to assist in the treatment of this disease.
Natural product screening is a term applied to the screening of natural environments for bioactive molecules. Particularly sought after bioactive molecules are those having potential as useful therapeutic agents. Natural environments include plants, microorganisms, coral and marine animals. The search for potential therapeutic agents for the treatment of cancer and infection by pathogenic organisms remains an important focus.
The Euphorbiaceae family of plants covers a wide variety of plants including weeds and other types of plants of Euphorbia species. There has been a variety of inconclusive reports on the potential effects of the sap of these plants on a range of conditions as well as promoting tumorigenesis and causing skin and ocular irritation.
The most intensively studied species of this group is Euphorbia pilulifera L (synonyms E. hirta L., E. capitata Lam.), whose common names include pill-bearing spurge, snakeweed, cat's hair, Queensland asthma weed and flowery-headed spurge. The plant is widely distributed in tropical countries, including India, and in Northern Australia, including Queensland.
A recent report describes selective cytotoxicity of a number of tigliane diterpene esters from the latex of Euphorbia poisonii, a highly toxic plant found in Northern Nigeria, which is used as a garden pesticide. One of these compounds has a selective cytotoxicity for the human kidney carcinoma cell line A-498 more than 10,000 times greater than that of adriamycin (Fatope et al., 1996).
Euphorbia hirta plants and extracts thereof have been considered for a variety of purposes, including tumor therapy (European Patent Application No. 0 330 094), AIDS-related complex and AIDS (Hungarian Patent Application No. 208790) and increasing immunity and as an anti-fungoid agent for treatment of open wounds (German Patent Application No. 4102054).
Thus, while there are isolated reports of anti-cancer activity of various Euphorbia preparations (see Fatope et al., 1996; Oksuz et al., 1996), not only are the compounds present in at least one Euphorbia species reported to be carcinogenic (Evans and Osman, 1974; Stavric and Stolz, 1976; Hecker, 1970), but at least one species has a skin-irritant and tumor-promoting effect (Gundidza and Kufa, 1993) and another species reduces EBV-specific cellular immunity in Burkitt's lymphoma (Imal, 1994).
In accordance with the present invention, the inventors have identified chemical agents and fractions comprising these agents from a plant of the Euphorbiaceae family which are useful in the treatment and prophylaxis of prostate cancer in mammalian and in particular human subjects.